modalities added to identify the primary site. Multiple lesions were confirmed in the gastrointestinal tract. Endoscopy was performed to identify the lesions, and several lesions were observed protruding from the mucous membranes. However, the endoscopy specimens did not yield an accurate diagnosis because adequate samples were not acquired. Blood and urine tests revealed no functional activity caused by the tumors. Although the origin was not histopathologically confirmed with endoscopy, this patient was situationally diagnosed with nonfunctional NET originating from the duodenum, as demonstrated by the metastases in the mandible. (Oral Surg Oral Med Oral Pathol Oral Radiol 2015;119:e41-e48)
Neuroendocrine tumors (NETs) originate from hor- mone-producing cells. Neuroendocrine cells are found throughout the body in such organs as the gastroin- testinal tract, pancreas, and lungs. Well-differentiated NET was previously described as“carcinoid” until this labeling was clarified by the World Health Organiza- tion (WHO) classification. In 2010, the WHO indi- cated a new classification of NETs based on both the mitotic count and Ki67 index and introduced a grading
system (Grade 1 to Grade 3). The European Neuro- endocrine Tumor Society (ENETS) also proposed a grading system (G1, G2, and G3).1-3 According to their proliferative activity, G1 and G2 neuroendocrine tumors are well differentiated, and G3 tumors are poorly differentiated and are called carcinomas (NECs). The diagnosis of a NET is based on the his- topathology of tumor specimens, circulating bio- markers, and imaging.2
Most NETs are located in the gastrointestinal tract and the pancreas. The incidence has been estimated to range from 1 to 2 per 100,000 people in Western countries.4,5In Japan, the latest report on the status of gastroenteropancreatic NETs (GEP-NETs) in 2005 estimated their prevalence to be 3.45 in 100,000 per- sons, with an annual onset incidence of 2.10 in
aAssistant Professor, Department of Comprehensive Dentistry, Insti- tute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
bAssociate Professor, Department of Oral Surgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
cProfessor and Chairman, Department of Comprehensive Dentistry, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
dAssistant Professor, Department of Oral Surgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
eAssistant Professor, Department of Oral molecular pathology, Insti- tute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
fProfessor and Chairman, Department of Oral molecular pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
gClinical Fellow, Department of Oral Surgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
hProfessor and Chairman, Department of Oral Surgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
Received for publication Mar 28, 2014; returned for revision Jul 22, 2014; accepted for publication Sep 21, 2014.
Ó 2015 Elsevier Inc. All rights reserved.
2212-4403/$ - see front matter
http://dx.doi.org/10.1016/j.oooo.2014.09.024
Statement of Clinical Relevance
Neuroendocrine tumors (NETs) are extremely rare and arise from the secretory cells of diffuse neuro- endocrine cells. These tumors are particularly rare in the oral and maxillofacial region, and only a few cases have been reported. NETs are classified as malignant tumors because of their metastatic char- acter. However, the malignant features are difficult to diagnose from the imaging findings in well- differentiated NETs because the tumors grow very slowly and the patients lack severe clinical symp- toms. In this article, we report a case of NET (Grade 2 in the World Health Organization 2010 classifi- cation) in the mandible.
e41
100,000.6The increase in the incidence of GEP-NETs during the last 30 years can be attributed to the increase in the detection rate due to advances in endoscopic and imaging methods.7-9
This report describes an NET in the mandible and includes imaging and pathologic findings, symptoms, and the process leading up to diagnosis. In this case, despite having extensive bone swelling and resorption, the patient did not have numb chin syndrome or trismus. Hence, this lesion was difficult to diagnose as a malignancy. NETs in the head and neck region, particularly the well-differentiated types, are often underdiagnosed.10
CASE REPORT
A 58-year-old woman visited a dental practitioner for a new denture and was taken for a dental impression. After 10 days, she visited the dentist again because a bleeding mass had appeared in the left buccal mucosa. She was referred to a hospital for further examination.
Her left cheek was swollen, and a 20 15 15 mm reddish brown bleeding mass (Figure 1) was observed on the left buccal mucosa. Trismus, paresthesia, and spontaneous pain were absent, and her lymph nodes were not palpable. She
had a history of hypertension and hyperthyroidism. Her father had died at 83 years of age from pancreatic cancer, and her sister had died of colorectal cancer.
Panoramic radiography revealed an ill-circumscribed, multilocular, radiolucent area in a honeycomb pattern around the left ramus of the mandible, which was bulging and dis- playing a thin cortical bone (Figure 2). Contrast-enhanced CT demonstrated a weakly enhanced lesion, which had a rela- tively clear boundary, around the left ramus. Moreover, the lesion was accompanied by sporadic bone destruction enlarged in the lingual and buccal directions, along with compressive bone resorption at the posterior part of the maxilla (Figure 3).
The patient had undergone magnetic resonance imaging (MRI) for torticollis 3 years ago, and a mass had been confirmed in the left mandibular ramus at that time. The lesion was observed as a round, homogeneous, well-demarcated mass on the T1-weighted image. Furthermore, the lesion showed iso-signal intensity to the parotid gland on a T2- weighted image (Figure 4, A and B).
Fig. 1. Intraoral photography revealing an easily bleeding mass in the left buccal mucosa.
Fig. 2. Panoramic radiograph showing a large, ill-defined, soap bubbleelike radiolucency of the left mandible extending from the retromolar area to the ramus.
Fig. 3. Contrast-enhanced CT showing a very large osteolytic lesion in the left ramus. A, axial image. B, coronal image.
In this consultation, MRI was used to determine if the patient’s hyperthyroidism was the result of a malfunctioning pituitary gland (see Figure 4, C and D). Although the mandibular lesion was not imaged, its total volume had remarkably increased compared with the volume of the lesion observed on MRI 3 years ago. The lesion was comparatively homogeneous and had a comparatively well-demarcated margin with a capsule, despite the remarkable bulging. These findings were similar to those found on CT (Figure 3).
On the basis of the clinical features and these imaging findings, the lesion likely originated from the intraosseous component of the mandible and was a benign or mildly ma- lignant tumor, such as a hemangioma (arteriovenous malfor- mation), odontogenic myxoma, keratocystic odontogenic tumor, or ameloblastoma.
A biopsy of the mandible was performed. Diffuse growth of tumor cells with nesting or necrosis was found. The cyto- plasm of large tumor cells was clear or granular, and abnormal nuclei and mitoses were detected. Thefibrosis and prolifera- tion of the capillary vessels were clearly evident in the stroma.
In addition, the immunohistochemical staining was positive for synaptophysin, chromogranin A, CAM5.2, S100, Ki-67 (10%), and vimentin, but not for CD 34, factor VIII, oraSMA (Figure 5, A-E; andTable I). On the basis of these results, the
intraoral lesion was diagnosed as Grade 2 NET based on the 2010 WHO classification (Table II). In addition, an immu- nohistologic study of somatostatin receptors (SSTR) was added to determine the treatment plan, and the specimen was positive for SSTR type 2 A (seeTable I).
After establishing the diagnosis, an extensive search for the primary site was conducted. Using positron emission to- mography (PET)-CT with 2-[fluorine 18] fluoro-2-deoxy-D- glucose (18F-FDG), the accumulation of FDG in the lesion was observed. The standardized uptake value ranged from 2.3 to 5.2. The maximum standardized uptake value of 5.2 was observed in the posterior wall of the maxillary sinus (Figure 6). Some nodular lesions were observed near the left posterior diaphragm and the posterior vestibular part of the stomach but did not show 18F-FDG accumulation. Subse- quently, abdominal contrast-enhanced CT and gastrointestinal endoscopy were performed. On the endoscopy, intramural multiple masses were observed in the gastrointestinal tract.
The overlying gastrointestinal mucosa was intact at some sites, and some masses showed focal ulceration. However, an adequate tissue sample for pathologic evaluation was not obtained from the endoscopy.
Considering the possibility of a paraganglion tumor, labeled meta-iodobenzylguanidine (MIBG) scintigraphy was Fig. 4. Magnetic resonance imaging scans, taken 3 years before (A and B) and during this consultation (C and D). B, T1-weighted image by fast spin echo method. B, T2-weighted image by fast recovery fast spin echo method. C, Gadolinium-enhanced T1- weighted image by spin echo method. D, T2-weightened image by fast spin echo method.
subsequently performed. On MIBG scintigraphy, the uptake was observed at the adrenal medulla (Figure 7). However, investigations for amine secretions, including urinary nor- metanephrine and metanephrine, which are the metabolites of normetanephrine and epinephrine, and 5-hydroxy indol acetic acid, were within normal ranges. Therefore, pheochromocy- toma, paraganglioma, and carcinoid tumors were excluded.
The blood hormone levels were normal; thus, a nonfunctional neuroendocrine tumor of the gastrointestinal tract was un- likely. Urine and hematologic assessment showed normal functional activity. No signs of paraneoplastic syndrome, such as hormone production, were observed.
Thefirst-choice treatment for NET is resection. However, in this case, the oral tumor was too large to be removed.
Attempted surgery would have reduced important functions, such as deglutition, speech, and eating, and affected the pa- tient’s quality of life. Instead, hormonal therapy was selected.
The intraoral specimen was positive for SSTR. Hence, a so- matostatin analog was administered during hospitalization around one month. A subcutaneous injection of 100mg san- dostatin was given twice daily. After the patient was dis- charged from the hospital, the injection was changed to the intramuscular long-acting Sandostatin LAR at 30 mg once a month. The patient continues to receive this therapy.
At present, the tumor has not reduced in size and no ab- normalities in the hormone levels have been observed.
DISCUSSION Definition
NETs are extremely rare tumors arising from the neuroendocrine cells. All NETs are potentially malig- nant but differ in their biologic characteristics and the probability of metastatic disease.11Neuroendocrine tu- mor cells secrete a variety of (poly-) peptide hormones, neuropeptides, and neurotransmitters. Functional tu- mors cause typical hypersecretion-related symptoms, which are directly related to the hormones secreted by Fig. 5. Histopathologic findings. A, Hematoxylin and eosin stain (magnification 100). B, Cytokeratin (CAM2.5) (magnification 100). C, S100 (magnification 100). D, Synaptophysin (magnification 100). E, Chromogranin A (magnification 100). F, Ki67 (magnification 40).
Table I. Results of immunostaining
Immunostaining Result
Synaptophisin Positive
Chromogranin A Positive
S100 Positive
CAM 5.2 Positive
EMA Weak positive
Vimentin Positive
Ki67 10% positive
CD34 Negative
Factor VIII Negative
aSMA Negative
Somatostatin receptor 2A Positive
Somatostatin receptor 5 Negative
the tumor, such as gastrinoma, insulinoma, glucago- noma in the pancreas, or carcinoid syndrome in patients with NETs of the ileum. Nonfunctional tumors do not secrete a hormone that results in a clinical syndrome.
On the other hand, as nonfunctional tumors do not secrete a hoemone, they are usually asymptomatic.
Thus, diagnosis of nonfunctional NETs tend to be difficult when they are small.
Classification
In 2010, the WHO defined low- to high-grade neuro- endocrine cancer types under the broad category of neuroendocrine neoplasms. The proposed WHO 2010 grading system places them into three classes based on both mitotic count and Ki67 index.1,2 The ENETS is- sued a GEP-NETs Ki67 labeling index.12 Table II shows the grading systems of GEP-NETs based on the ENETS and WHO guidelines. Grade 1 shows a low proliferative index (Ki67 <3% or <2 mitoses per 10 high-powerfield), Grade 2 shows a moderate prolifer- ative index (Ki67 3%-20% or 2-20 mitoses per 10 high- power fields [hpf]), and Grade 3 shows a high
eration13; it is strongly associated with cell prolifera- tion. Ki-67 protein is present during all active phases, such as the G1, S, G2, and M phases of the cell cycle, but is absent in resting cells (G0 phase).13In addition, Ki67 protein and the degree of the malignancy of the tumor are closely related; thus, Ki67 is a useful marker to detect proliferation in the tumor. The proliferative rate can also be assessed on the basis of the number of mitoses per unit area of tumor (mitoses per 10 hpf or per 2 mm2). Ki67 is the biologic marker of cell pro- liferation, and the mitotic count represents morphologic changes in the nucleus. Ki67 is somewhat easier to evaluate than the mitotic count and more useful when the volume of tissue is limited.
Etiology
The incidence of NETs has been estimated to range from 1 to 2 per 100,000 people in Western countries.4,5 In Japan, the latest report on the status of GEP-NETs in 2005 estimated the prevalence at 3.45 per 100,000, with an annual onset incidence of 2.10 per 100,000.6With regard to prognosis, Panzuto et al. reported that the overall 5-year survival rate of patients with NETs was 77.5%, and the major negative prognostic factors are pancreatic site, a poor degree of tumor cell differenti- ation, and distant extrahepatic metastases.14 Further- more, Pape et al. reported that the overall 2-year, 5-year, and 10-year survival rates were 87%, 75%, and 64%, respectively.4
According to Ito et al., the age of onset of gastroin- testinal NETs is 50 to 70 years in 70.9% of patients, and mean age of onset was 59.8 years (males, 61.3; females, 57.3). Of the patients in the study, 64% were male and 32.3% were female, and 3.6% did not have information on the gender.6In a survival analysis of NETs classified according to the WHO grading system, the survival period was significantly poorer for patients who had G3 tumors than for those who had G1 and G2 tumors.4 Imaging diagnosis
The role of imaging with regard to functional NETs is mainly to detect the number of tumors and their locations Fig. 6. The 18F-fluorodeoxyglucose positron emission
computed tomography shows the standardized uptake value maximum at 5.2 around the posterior wall of the maxilla.
because clinical symptoms are already apparent due to the hormones secreted by the tumor. In contrast, with nonfunctional NETs, which manifest late as large masses that cause compression syndromes or incidental findings, imaging is not primarily aimed at tumor detection.15 Nonfunctional tumors frequently present late with mass effects, as they lack accompanying clin- ical syndromes. Once functional or nonfunctional NETs are suspected or diagnosed, a systemic whole body ex- amination using PET/CT and scintigraphy is needed to identify a primary tumor or a metastatic tumor.
In the present case, we initially did not consider the lesion to be malignant. On radiographic examination, remarkable bone destruction and swelling of the left side of the mandible were observed. On CT, the border of the tumor was relatively clear, and compressive bone resorption in the posterior bone wall of the left maxilla was observed, rather than invasive destruction, which is a sign of malignancy. Furthermore, the patient did not have clinical manifestations, such as mandibular nerve paralysis, trismus, and pain, despite the extensive bone destruction. According to these imaging and clinical findings, we diagnosed the lesion as a benign tumor that originated from the mandible, such as an arteriovenous malformation, odontogenic myxoma, keratocystic odontogenic tumor, or ameloblastoma. Because the lesion was clarified as an NET on biopsy, whole-body
scanning was performed. Wefinally detected the pri- mary site using [18 F] FDG-PET-CT. Some nodular lesions in the gastrointestinal tract were confirmed on CT, although the mass did not show [18F] FDG uptake.
However, a previous report indicated that PET with
18F-FDG is not useful for NETs, except for highly aggressive tumors.16,17Castano et al. stated that the vast majority of NETs with low Ki67 expression are, indeed, [18F] FDG PET negative.18In the present case, PET-CT was useful in detecting the primary sites and staging the NETs. Various nodular lesions were found in the duo- denum on PET/CT; thus, endoscopy was added.
PET-CT can reveal both anatomic and metabolic in- formation, irrespective of FDG uptake. Therefore, we suggest the use of PET/CT as a sensitivefirst-line im- aging modality to detect the primary sites when a neuroendocrine tumor is suspected. Even though FDG was used for PET/CT at our institution, a new tracer for the diagnosis of NETs deserves attention. New PET tracers, such as 68Ga-DOTATOC, 68Ga-DOTATATE, and 68Ga-DOTANOC, which utilize somatostatin re- ceptors as the target, have been developed.19
Somatostatin receptor scintigraphy is a standard method to image NETs in some countries but not in Japan. This imaging method uses In-111 pentereotide, which is a homolog of somatostatin and can detect somatostatin receptors SSTR2 and SSTR5) developing Fig. 7. Adrenal scintigraphy labeled meta-iodobenylguanidine. A, Full body image (left: frontal view; right: posterior view). B, Enlargement of abdominal area (frontal view). C, Enlargement of abdominal area (posterior view). Other than the liver and gastrointestinal physiologic uptake, multiple uptakes were observed at the abdominal nodules, which were also observed in the computed tomography examination. Although uptake at the left parotid area was observed, it was unclear whether this uptake was caused by the tumor itself or was due to a physiologic change in the parotid caused by the tumor.
the major member of a family of acidic glycoproteins that are secreted from almost all endocrine and neuroendocrine cells of mammalian tissue, including the adrenal gland, endocrine pancreas, gastrointestinal endocrine system, thyroid gland, parathyroid gland, and pituitary gland.24,25 Synaptophysin has been identified as a component of the membrane in pre- synaptic vesicles and a sensitive marker for neuroen- docrine tumors.26Chromogranin A is the most widely used marker of neuroendocrine differentiation,21 and synaptophysin is a sensitive but nonspecific marker expressed by adenomas and carcinomas of the adrenal cortex and normal cells.23Recently, the plasma levels of chromogranin A were reported to be the most consistent general marker of NETs, showing high sensitivity and specificity and reflecting the clinical evolution of the disease.27
Treatment
At present, the early detection and surgical resection of the tumor represents the best chance for a cure.28 However, the majority of patients with sporadic GEP- NETs present with locally advanced, unresectable dis- ease, frequently with distant metastases, and currently, there is no curative therapy.28 Other available treat- ments include chemotherapy, interferon, somatostatin analogues, and targeted therapies.29-33
For treatment with somatostatin analogs, the distinc- tion of the somatostatin receptor (SSTR5 or SSTR2) is very important. Somatostatin, which is a peptide hor- mone produced by the hypothalamus, inhibits the release of growth hormones and other secretory proteins.34So- matostatin analogs are the best therapeutic option for functional NETs because they reduce hormone-related symptoms and also have antitumor effects.35 Somato- statin analogs are considered optional for treating nonfunctional tumors. They were found to have disease- stabilizing effects,36but data from a placebo-controlled trial in pNET are still pending (CLARINET study [Controlled study of Lanreotide Antiproliferative Response In NeuroEndocrine Tumors]). In the present case, the lesion that metastasized to the mandible was
body imaging, the origin of these lesions (i.e., primary or metastatic) was ambiguous. A NET of the mandible was reported by Colman et al.; however, it did not have the histologic or immunohistochemical charac- teristics of a paraganglioma, and the cell of origin was unknown.37The authors presumed that the tumor must have originated from immature, functionally uncom- mitted endocrine cells that were derived from the most proximal part of the foregut.37 This case was very similar to our present case, and we doubt that it was a metastatic case. If a systemic search had been carried out, the origin of the NET might have been proven.
The current report describes a neuroendocrine tumor in the mandible. The tumor had grown to a very large size and caused destruction to the mandible, but the bone destruction was rather benign. Furthermore, the patient did not report symptoms, such as pain or paresthesia. The diagnosis of a neuroendocrine tumor is very difficult malignant bone destruction and clinical signs cannot be detected, and most dentists are not familiar with NETs.
REFERENCES
1.Klimstra D, Modlin I, Coppola D, Lloyd R, Suster S. The patho- logic classification of neuroendocrine tumors a review of nomen- clature, grading, and staging systems. Pancreas. 2010;39:707-712.
2.Oberg K, Castellano D. Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev.
2011;30:3-7.
3.Klimstra DS. Pathology reporting of neuroendocrine tumors:
essential elements for accurate diagnosis, classification, and staging. Semin Oncol. 2013;40:23-36.
4.Pape U, Jann H, Muller-Nordhorn J, et al. Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors. Cancer. 2008;113:256-265.
5.Plöckinger U, Rindi G, Arnold R, et al. Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS). Neuroendocrinology. 2004;80:394-424.
6.Ito T, Sasano H, Tanaka M, et al. Epidemiological study of gastroenteropancreatic neuroendocrine tumors in Japan.
J Gastroenterol. 2010;45:234-243.
7.Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003;97:934-959.
8.Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Cur- rent status of gastrointestinal carcinoids. Gastroenterology.
2005;128:1717-1751.
9.Yao JC, Hassan M, Phan A, et al. One hundred years after
“carcinoid”: epidemiology of and prognostic factors for neuro- endocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063-3072.
10.Mills S. Neuroectodermal neoplasms of the head and neck with emphasis on neuroendocrine carcinomas. Mod Pathol. 2002;15:
264-278.
11.Sahani DV, Bonaffini PA, Fernández-Del Castillo C, Blake MA.
Gastroenteropancreatic neuroendocrine tumors: role of imaging in diagnosis and management. Radiology. 2013;266:38-61.
12.Rindi G, Klöppel G, Couvelard A, et al. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2007;451:757-762.
13.Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000;182:311-322.
14.Panzuto F, Nasoni S, Falconi M, et al. Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocr Relat Cancer.
2005;12:1083-1092.
15.Rockall AG, Reznek RH. Imaging of neuroendocrine tumours (CT/
MR/US). Best Pract Res Clin Endocrinol Metab. 2007;21:43-68.
16.Adams S, Baum R, Rink T, Schumm-Drager P, Usadel K, Hor G.
Limited value offluorine-18 fluorodeoxyglucose positron emis- sion tomography for the imaging of neuroendocrine tumours. Eur J Nuclear Med. 1998;25:79-83.
17.Kauhanen S, Seppänen M, Ovaska J, et al. The clinical value of [F-18]fluoro-dihydroxyphenylalanine positron emission tomog- raphy in primary diagnosis, staging, and restaging of neuroen- docrine tumors. Endocr Relat Cancer. 2009;16:255-265.
18.Castao JP, Sundin A, Maecke HR, et al. Gastrointestinal neuro- endocrine tumors (NETs): new diagnostic and therapeutic chal- lenges. Cancer Metastasis Rev. 2014;33:353-359.
19.Virgolini I, Ambrosini V, Bomanji JB, et al. Procedure guidelines for PET/CT tumour imaging with Ga-68-DOTA-conjugated pep- tides: Ga-68-DOTA-TOC, Ga-68-DOTA-NOC, Ga-68-DOTA- TATE. Eur J Nuclear Med Mol Imag. 2010;37:2004-2010.
20.Turaga KK, Kvols LK. Recent progress in the understanding, diagnosis, and treatment of gastroenteropancreatic neuroendo- crine tumors. CA Cancer J Clin. 2011;61:113-132.
21.Chang S, Choi D, Lee SJ, et al. Neuroendocrine neoplasms of the gastrointestinal tract: classification, pathologic basis, and imaging features. Radiographics. 2007;27:1667-1679.
22.Kasprzak A, Zabel M, Biczysko W. Selected markers (chro- mogranin A, neuron-specific enolase, synaptophysin, protein gene product 9.5) in diagnosis and prognosis of neuroendocrine pul- monary tumours. Pol J Pathol. 2007;58:23-33.
23.Lloyd RV. Practical markers used in the diagnosis of neuroen- docrine tumors. Endocr Pathol. 2003;14:293-301.
24.Rindi G, Buffa R, Sessa F, Tortora O, Solcia E. Chromogranin A, B and C immunoreactivities of mammalian endocrine cells.
Distribution, distinction from costored hormones/prohormones and relationship with the argyrophil component of secretory granules. Histochemistry. 1986;85:19-28.
25.Fujiyoshi Y, Eimoto T. Chromogranin A expression correlates with tumour cell type and prognosis in signet ring cell carcinoma of the stomach. Histopathology. 2008;52:305-313.
26.Wiedenmann B. Synaptophysin. A widespread constituent of small neuroendocrine vesicles and a new tool in tumor diagnosis.
Acta Oncol. 1991;30:435-440.
27.Campana D, Nori F, Piscitelli L, et al. Chromogranin A: is it a useful marker of neuroendocrine tumors? J Clin Oncol. 2007;25:
1967-1973.
28.Meeker A, Heaphy C. Gastroenteropancreatic endocrine tumors.
Mol Cell Endocrinol. 2014;386:101-120.
29.Ferlito A, Rinaldo A. The spectrum of endocrinocarcinomas of the larynx. Oral Oncol. 2005;41:878-883.
30.Ochsenreither S, Marnitz-Schultze S, Schneider A, et al.
Extrapulmonary small cell carcinoma (EPSCC): 10 years’ multi- disciplinary experience at Charite. Anticancer Res. 2009;29:
3411-3415.
31.Brennan SM, Gregory DL, Stillie A, Herschtal A, Mac Manus M, Ball DL. Should extrapulmonary small cell cancer be managed like small cell lung cancer? Cancer. 2010;116:888-895.
32.Dahan L, Bonnetain F, Rougier P, et al. Phase III trial of chemotherapy using 5-fluorouracil and streptozotocin compared with interferon alpha for advanced carcinoid tumors: FNCLCC- FFCD 9710. Endocr Relat Cancer. 2009;16:1351-1361.
33.Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo- controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27:4656-4663.
34.Oberg K. Somatostatin-receptor mediated diagnosis and treatment in gastrointestinal neuroendocrine tumours (GEP-NET’s). Rocz Akad Med Bialymst. 2005;50:62-68.
35.Oberg KE, Reubi JC, Kwekkeboom DJ, Krenning EP. Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy. Gastroenterology. 2010;139:742-753:
753.e1.
36.Modlin IM, Pavel M, Kidd M, Gustafsson BI. Review article:
somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Thera- peutics. 2010;31:169-188.
37.Coleman H, Kennedy M, Altini M, Crooks J, Tsakiris P.
Neuroendocrine (carcinoid) tumor of the mandible: a case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;81:74-78.
38.Yang S, Chen S, Chen X, Long X. Primary typical carcinoid tumour in the retromolar region with prominent squamous dif- ferentiation: a case report. Int J Oral Maxillofac Surg. 2011;40:
991-994.
39.Peters E, Richards A, Hille J, Phillips J. Malignant neuroendo- crine tumor presenting in the mandible. Head Neck. 1991;13:
234-238.
40.Salama AR, Jham BC, Papadimitriou JC, Scheper MA. Metastatic neuroendocrine carcinomas to the head and neck: report of 4 cases and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;108:242-247.
41.Miki K, Orita Y, Nose S, et al. Neuroendocrine carcinoma of the larynx presenting as a primary unknown carcinoma. Auris Nasus Larynx. 2012;39:98-102.
Reprint requests:
Chieko Sugawara, DDS, PhD
Human Development and Health Science Department of Oral Health Science Comprehensive Dentistry Institute of Health Biosciences
The University of Tokushima Graduate School 3-18-15 Kuramoto-cho Tokushima city Tokushima 770-8504
Japan
Sugawara@tokushima-u.ac.jp
